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The limited preclinical testing and absence of any clinical demonstration of mGluR5 activation as a therapeutic target in schizophrenia temper enthusiasm. However, the demonstrated ability to enhance NMDA receptor signaling at the neuronal level will encourage the future development and testing of mGluR5 ligands. GABAA receptors as therapeutic targets for schizophrenia GABAergic pathology in schizophrenia There is now substantial evidence that GABA signaling is deficient in corticolimbic regions, particularly

in the dorsal lateral prefrontal cortex (DLPFC) and hippocampus, of patients with schizophrenia. One of the most consistent postmortem findings in schizophrenia is Inhibitors,research,lifescience,medical a reduction in the mRNA expression level of GAD67 in PV+-GABAergic interneurons, as well as reductions in PV expression itself.172 PV+ interneurons Inhibitors,research,lifescience,medical exhibit fast-spiking firing click here properties and target the spike -initiating region of pyramidal neuron axons, and are therefore thought to play a key role in controlling the overall firing properties of brain networks. Recent pharmacological, Inhibitors,research,lifescience,medical immunological, and genetic evidence from animal models suggests that inflammatory cytokine exposure (increased oxidative

stress) and NMDA receptor hypofunction occurring during cortical development leads to permanent disturbances in neuronal circuits, specifically in the population of PV-containing interneurons.173 The reduced GABA signaling by PV+-interneurons onto pyramidal neurons could contribute to the working memory deficits observed in schizophrenia. PVinterneurons control the rate of pyramidal cell firing, thereby synchronizing oscillatory activity of cortical pyramidal neurons in

the gamma band range (30 to Inhibitors,research,lifescience,medical 80 Hz).174 Gamma oscillations regulate working memory and the transmission of information between cortical regions. Inhibitors,research,lifescience,medical Therefore, it is hypothesized that the asynchronous pyramidal neuronal activity resulting from aberrant PV+ GABAergic signaling contributes to the cognitive dysfunction observed in schizophrenia. It is because of this hypothesis that GABAA receptors are now being considered a viable pharmacologic target for treating the cognitive disturbances associated with schizophrenia.172 GABAA receptors are membrane proteins that form a heteropentameric GABA-gated chloride Etomidate channel, which mediate largely tonic and phasic inhibition. They are composed of several classes of subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π, ρ1-3), but generally consist of three types of subunits (α, β, γ). The majority of GABAA receptors are characterized by their sensitivity to benzodiazepines. These receptors contain subunits (α1, α2, α3, or α5), a β subunit (mainly β2 or β3), and in almost all cases the γ2 subunit in a 2:2:1 stoichiometry. Benzodiazepineinsensitive receptors contain α4, α6, or δinstead of γ2.

The group led by Beattie has demonstrated that TNF-a induces the expression of glutamatergic receptors of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole pro prionate) type on neuronal axons.118 Inhibition of the TNF-α signal by specific antibodies or soluble receptors lead to a reduced AMPA receptor expression. These cytokine activities may be involved in the ability of cytokines

to alter the neural processes of learning.119,120 Besides the direct action Inhibitors,research,lifescience,medical of cytokines on brain cells, a biochemical link between cytokines and 5-HT is provided by the IFN-γ-controlled tryptophan metabolism. The essential amino acid tryptophan is the precursor of two distinct metabolism pathways, leading to the products 5-HT or kynurenine (Figure 2) The enzyme indoleamine-2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, which is then converted to quinolinic acid by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are Pexidartinib induced by IFN-γ. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation.121 Inhibitors,research,lifescience,medical It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan.122 The Th2 cytokines IL-4 and IL-10 inhibit the IFN-β-induced

tryptophan catabolism by IDO.123 The enzyme IDO is located in several cell types including monocytes and microglial cells.124 Thus, an IFN-yinduced, IDO-mediated decrease in CNS tryptophan availability may lead Inhibitors,research,lifescience,medical to a serotonergic deficiency. Figure 2. The essential amino acid tryptophan is converted either into the neurotransmitter serotonin, or into the neuroactive metabolite Inhibitors,research,lifescience,medical kynurenine, which is further degraded to quinolinic acid. The rate-limiting enzyme in the kynurenine pathway, indoleamine2,3-dioxygenase … Cytokines and psychiatric symptoms Sickness behavior The IL-1 receptor was the first cytokine-related

structure detected in the brain.125,126 In 1988, the group led by Dantzer demonstrated the functional relevance of IL-1 and its receptor in the brain: IL-1 injected into the Inhibitors,research,lifescience,medical brain of rats induced conditioned taste aversion.127 In the same year, the effect of another cytokine, TNF-α, was introduced, when the group of Plata-Salaman showed the suppressing Oxymatrine effect of IL-1 and TNF-α on feeding behavior.128 Later, it was shown that peripherally administered LPS induces the expression of IL-1α, IL-1β, TNF-α, and IL-6 in brain macrophages and microglia.129-131 This effect seems to be a key mechanism in the induction of non-specific sickness symptoms including fever, anorexia, hyperalgesia, and the so-called sickness behavior, which is characterized by weakness, malaise, Hstlessness, cognitive impairment, depressed mood, lethargy, and reduced feeding behavior.132 Behavioral changes during cytokine therapy The first indication of a role for cytokines in sickness behavior in humans came from clinical trials in which recombinant or purified cytokines were used to treat specific cancers or chronic viral infections such as hepatitis B or C.

​(Fig.2424). Figure 24 Performance of WT and SOD1 www.selleckchem.com/products/otx015.html mutant mice on the loaded grid test. Performance is based on the duration of time in seconds (sec) before the loaded grid was dropped. (A) Each mouse was tested twice with a 15 g weight and allowed unlimited time before dropping … Discussion Sporadic ALS and SOD1 mutant forms of FALS are clinically indistinguishable. Mice and rats expressing mutant forms of human SOD1 develop progressive MN degeneration and clinical signs that closely mimic sporadic and familial forms of human ALS (Gurney et al. 1994). Initial characterization

of the animal models understandably focused Inhibitors,research,lifescience,medical on pathological events associated with obvious behavioral symptoms (e.g., leg tremor) and MN degeneration. The onset of overt clinical symptoms in the SDO1G93A mouse is generally reported to occur at approximately P90, but see (Mancuso et al. 2011; Mead et al. 2011; Gerber et al. 2012). We find that signs of axonal Inhibitors,research,lifescience,medical degeneration are evident by Inhibitors,research,lifescience,medical P75, but the absolute number of ventral root axons is still comparable with WT. The MNs that will die can be identified by P60 even though their removal from the spinal cord does not occur until later ages. Consistent with previous reports, we confirm that muscle denervation long precedes activation of cell death pathways and the classical definition of clinical

the onset of denervation Inhibitors,research,lifescience,medical at P25–30, 10–20 days earlier than previous reports. As demonstrated previously Inhibitors,research,lifescience,medical (Pun et al. 2006; Hegedus et al. 2007), denervation does not occur uniformly in all muscles but is dependent on fiber type with fast fibers being denervated before slow fibers. Here, we report that denervation of the TA muscle occurs between P14 and P30, while at the same time little denervation occurs in the soleus muscle that is composed primarily of slow fibers. Muscle denervation during the first postnatal Calpain month calls into question previous characterization of the SOD1G93A mouse model in terms of disease onset. Traditionally, disease onset was considered to occur in the third postnatal month, a time coincident with detection of MN cell death; however, here we also provide evidence that motor function deficits begin coincident with initial muscle denervation. Muscle strength, as assessed by the loaded grid test and treadmill gait was impaired in mutant mice beginning around P30–40 and treadmill deficits only occurred in mice walking uphill at increased speeds when the TA muscle is increasingly engaged (Roy et al. 1991).

Comparatively high rates of depression arc found in community prevalence studies.33 It is not clear whether all these depressions share fully the qualities of depression presenting for medical or psychiatric treatment. Similar issues

arise in the use of “symptomatic volunteers” for research. There have been a number of studies examining boundaries of DSM major depression.11,12,34-36 These do support the validity of summing the number of symptoms, although it is doubtful whether there is any true threshold rather than a somewhat arbitrary cutoff on a continuum, Inhibitors,research,lifescience,medical and one which as defined may be a little too high. In terms of treatment response, there is good evidence of a threshold, a little below major depression, at which superiority of Inhibitors,research,lifescience,medical tricyclic antidepressants to placebo first appears.37 The threshold for response to serotonin reuptake inhibitors may be a little lower.38 Dysthymia and subsyndromal depression Dysthymia was introduced into official classifications in DSM-III, using a term which had been originated by the 19th-century French Inhibitors,research,lifescience,medical psychiatrist, Janet. The concept had previously been introduced for research in

the predecessor of DSM-III, The Research Diagnostic Criteria, as Intermittent Depression.39 Partly the use of the term was to avoid use Inhibitors,research,lifescience,medical of the term neurotic depression. It reflected the wider modern trend to view such

chronic phenomena as primarily disorders of mood rather than of personality. In the last 20 years dysthymia has proved a useful concept, delineating a form of mood disorder which can produce many problems and have an adverse impact on the life of the sufferer, and it has generated much research.40 There is a high rate of comorbidity, particularly of Inhibitors,research,lifescience,medical anxiety disorders and substance abuse. The majority of dysthymics ultimately also develop an episode of major depression, and such episodes, so-called double depression, have a worse prognosis than pure major depression, both in respect of remission and of recurrence. There appears therefore to be continuity between dysthymia and major depression. The DSM-IV definition rules out an episode of major depression Casein kinase 1 in the first 2 years, but the ICD-10 definition does not. In practice the trans-isomer ic50 differentiation of dysthymia from milder chronic major depression or from the residual symptoms with partial remission which frequently occur after major depression,41 is difficult and may be artificial. There is evidence that dysthymia responds to antidepressants,42 but controlled trials do not always distinguish uncomplicated dysthymia from superimposed major depression.

seen in the peripheral blood of patients with acute ischemic stroke and we confirmed an increase of EPC levels in the subacute stage. Significantly, patients who were receiving statins at the time of stroke had higher EPC levels. The presence of EPC may improve the outcome of certain stroke subtypes, that is, large-artery atherothrombosis and small-vessel disease. We consider that the precise mechanisms by which EPC are associated with outcome deserve further studies. Further selleck screening library studies should Inhibitors,research,lifescience,medical explore whether EPC may have a therapeutic role in ischemic stroke. Acknowledgments We thank Professor William Stone (Hospital de la Santa Creu I Sant Pau) for helpful comments and editing the manuscript. Conflict of Interest None declared.Please note that an article related to this editorial, “The role of remote ischemic preconditioning

in the treatment of atherosclerotic diseases,” doi: 10.1002/brb3.161, can be found here, also Inhibitors,research,lifescience,medical published in Brain Inhibitors,research,lifescience,medical and Behavior. The best-laid schemes o’ mice an’ men, Gang aft agley, An’ lea’e us nought but grief an’ pain for promis’d joy! –To a Mouse by Robert Burns (1785) In this issue of Brain and Behavior, Vasdekis et al. (2013) thoroughly review the theory behind remote ischemic preconditioning and the results to date of its application among patients with atherosclerotic narrowing of arteries supplying various organs including the brain. In these various trials and Inhibitors,research,lifescience,medical observations, clinicians and researchers artificially created ischemia to limbs to reduce ischemic injury to organs threatened by preexisting atherosclerotic lesions. By doing so, Inhibitors,research,lifescience,medical they, in effect, created one pathological condition (albeit theoretically a completely reversible one) to treat another

persistent condition. I plan in this editorial to place ischemic preconditioning into a historical context, to critique its potential benefits, risks, and limitations, and to try to look ahead at its future applications if any. Rationale and Early Studies The idea behind creating one pathological condition to treat another dates back at least to Hippocrates who prescribed hot water and steam baths to create fever to treat spasticity and pain (Bierman 1942). Wagner-Jauregg received the Nobel Prize for inoculating malarial organisms GPX6 into individuals diagnosed with syphilitic general paresis (Bierman 1942); Brown-Sequard lit fire to the skin of the trunk to treat spinal cord injuries (McCullough 2011); doctors used bees to sting patients with multiple sclerosis. The unifying concept in creating a new problem was that pathological conditions induced changes in the body that might be effective in treating other preexisting conditions.

​(Fig.1).1). Although noted many years ago (12), the presence of autophagy has largely been ignored. It’s actually surprising that autophagy was not directly linked to

the pathogenesis of the disease. After all, the lysosome is the endpoint for both the endocytic pathway – the route of the recombinant enzyme to the lysosome, and the autophagic pathway. Figure 1 Electron microscopy Inhibitors,research,lifescience,medical of type I and type II fibers from a 9 month-old knockout mouse showing the presence of autophagic buildup in type II fiber. Autophagy is an evolutionarily conserved pathway of lysosomal degradation and recycling of long-lived proteins and damaged organelles (13), which maintains intracellular balance between biosynthetic and catabolic processes and is a critical survival mechanism under conditions of nutrient deprivation. Autophagy involves the formation of a double-membrane vesicle, which engulfs part of the cytoplasm and damaged organelles and then fuses with a lysosome where the content of the vesicle is degraded.

These double-membrane vesicles, known as Inhibitors,research,lifescience,medical autophagosomes, can be detected by staining with a highly specific marker, LC3 Inhibitors,research,lifescience,medical (14). Under normal conditions of productive autophagy, autophagosomes are quickly degraded by the lysosomes, and LC3-positive structures are barely detectable. To study the geographic distribution of the autophagic structures seen by electron microscopy in knockout fibers, we isolated single

muscle fibers, and stained them with LC3 as well as with lysosomal membrane protein LAMP1, which stains both late endosomes and lysosomes. Strikingly, the autophagic areas were huge, extending almost the full length of the fiber, and were often located in the center Inhibitors,research,lifescience,medical of the fiber. Once recognized, the autophagic areas could be clearly seen in fixed or live fibers without any staining by low resolution transmitted light microscopy (Fig. ​(Fig.2).2). In some fibers, the volume occupied Inhibitors,research,lifescience,medical by the autophagic buildup reached 40% of the total volume of the fiber (15). Figure 2 Autophagic area could be observed in type II fibers by low resolution transmitted light microscopy. Live cultured myofibers from predominantly type II gastrocnemius (pale) muscle of 2.5 month-old WT and KO mice. Confocal microscopy of immunostained KO single muscle fibers has revealed the presence of multiple already LC3-positive autophagosomes, LAMP1-positive late endosomes and lysosomes, as well as LC3/LAMP1 double-positive structures. The abundance of LC3-positive and LC3/LAMP1 double-positive structures indicates the failure of the lysosomes to fuse with and degrade the content of autophagosomes. Excessive clustering of the vesicles of the autophagic and endocytic pathway, as well as the accumulation of intralysosomal and extralysosomal undigested material, have profound effects on muscle BIBW2992 chemical structure architecture (11, 15).

Masking Changes in the environment (temperature or light intensity and duration), and changes in internal states and behaviors such as movement and immobility, learn more fatigue and sleep, hunger and eating, can modify the pattern of biological rhythms.38 These are known as masking effects,39 to indicate that the circadian or ultradian rhythms would differ in the absence of these factors. For example, going to sleep is accompanied by a decrease in core body temperature, while the contrary occurs at the time of physical or mental effort. Also, the circadian rhythm of TSH is more Inhibitors,research,lifescience,medical marked if subjects maintain their usual

feeding schedule and professional activities rather than staying in bed and receiving no food.40 Masking effects could in part explain the decreased amplitude in temperature and TSH circadian rhythms described in depressed patients by several authors,41 Inhibitors,research,lifescience,medical since these patients might have had a lower level of physical activity within the hospital. Social and lifestyle factors also play a role

in the measurable phenotype of biological clock physiology.42 The so-called constant routine studies enable to overcome or neutralize masking effects; in such studies, subjects lie recumbent in constant light and receive frequent snacks. These protocols are Inhibitors,research,lifescience,medical complex, but they are necessary to explore the functioning of the biological clock in manners that separate the endogenous and exogenous components of rhythms. Ontogeny and senescence of Inhibitors,research,lifescience,medical eniogenous rhythms Biological clocks play a role at the cellular level by modulating the rate of mitosis.43 At the macroscopic level, preterm infants of 35 weeks already have bouts of activity and sleep44 and, based on extrapolation from animal research, the human SCN might become sensitive to light around the sixth month of pregnancy,45 and even low levels of light, of 200 lux, entrain the SCN.46 After birth, a circadian periodicity of body temperature and other variables

is present at 1 month and develops over the following month.47 Children stabilize a circadian rather than an ultradian rhythm of wake-sleep around the age of Inhibitors,research,lifescience,medical 3 to 6 months,48 although differences in activity and sleep can be detected very soon after birth in some infants. Of note is the fact that the prenatal development of biological clocks is sensitive Dichloromethane dehalogenase to fetal exposure to teratogens and other toxins, such as alcohol.49 Circadian clock physiology can also be altered by postnatal maternal deprivation in rodents, and the changes persist into adulthood.50 According to the results of a survey of 25 000 inhabitants in Europe, there is a sudden change in sleep habits that marks the end of the tendency to sleep later during childhood and adolescence. Indeed, around the age of 20, most young adults tend to go to sleep and wake up earlier. Roenneberg and collaborators even suggested that this change could be a marker of the end of adolescence.

prefrontal activation. While the papers reviewed above are limited to interactions between a maximum of four SNPs, the complexity of common genetic variation related to schizophrenia, which is check details likely to include effects of thousands of variants, will require a methodological effort to characterize interactions between larger sets of genes as they impact on imaging data. Calhoun and coworkers employed parallel independent component analysis, applied to auditory Inhibitors,research,lifescience,medical oddball task fMRI data, and extracted a set of 10 SNPs that were significantly related to imaging data and differed between a sample of patients and controls.48 While selection of SNPs and small sample size preclude conclusions about the specific genes they highlighted, Inhibitors,research,lifescience,medical their study provides proof of concept of the applicability of multivariate methods in imaging genetics. Copy number variants An important insight that has emerged from the last waves of genome -wide studies of schizophrenia concerns structural variations of the genome, where larger segments (up to several megabases) of genetic material are either Inhibitors,research,lifescience,medical duplicated

(microduplications) or missing (microdeletions).49,50 Convergent evidence now shows that such copy number variants (CNVs) are more common in schizophrenia than in the general population. In contrast to frequent genetic variants such as SNPs, the risk associated with some CNVs is much higher, and can correspond to a tenfold increase in disease risk. Inhibitors,research,lifescience,medical There is evidence that the presence of these variants is deleterious since they are under negative selection.51 Several specific regions now have strong evidence for conferring risk for schizophrenia, mapping on chromosome regions at 22q11, 15q13.3, 1q21.1, 15q11.2, 17p12, 2p16.3, 16p13.1, and Inhibitors,research,lifescience,medical 16p11.2. One of these, 22q11, has been known for a longer

time since this microdeletion causes a clinical syndrome (velocardiofacial, DiGeorge, or 22q11 deletion syndrome) that is recognizable by a pattern of somatic symptoms, such as heart defects or cleft palate, in addition to the the increased risk for psychosis.52 An important research frontier will be to understand, using imaging genetics, how these microdeletions impact on brain structure and function. This work is farthest in 22q11DS, which has been known for the longest time. Here, convergent evidence implicates reductions in hippocampus and cerebellum, abnormal white matter connectivity, especially in the posterior corpus callosum, and reduced prefrontal activation (possibly compensated by parietal activation) during working memory tasks.

collected on patients who arrive at hospital alive and meet any of the subsequent criteria: – Death from injury at any point during admission – stay in hospital for longer than 3 days – require intensive or high dependency care – require inter – hospital transfer for specialist care Inhibitors,research,lifescience,medical Patients with isolated closed limb injuries are excluded, as are patients over 65 years with isolated fracture neck of femur or pubic ramus fracture. All other isolated closed femoral injuries are included. The details of the data collection process have been described in detail elsewhere. Briefly, data are collated by trained staff in participating hospitals and submitted via the TARN Electronic Data Collection and Reporting (EDCR) system (ref http://www.tarn.ac.uk). Each submission Inhibitors,research,lifescience,medical is checked for consistency and accuracy by trained

coders at the University of Manchester. All injuries are coded using the Abbreviated Injury Scale 1998 Dictionary which allocates each injury a severity code between 1 (minimal) and 6 (buy Small molecule library maximal). [11] AIS severity coding is derived from the precise injury descriptions given by imaging, operative and post mortem Inhibitors,research,lifescience,medical reports. Adult (age > 15 yrs at time of injury) patients presenting between 2001 and 2008 to TARN participating hospitals were included in the study dataset if they had a Glasgow Coma Score (GCS) less than 15 at presentation or any head injury with AIS severity code 3 and above. Only cases with known final

outcome were selected. Variables Inhibitors,research,lifescience,medical Main Exposure The extent of intracranial bleeding was determined from the AIS code. [11] IB was coded as epidural (EDH) subdural (SDH) and intraparenchymal (IPH). Each type was coded as absent, present small (AIS4), present large (AIS5) or present size unspecified (AIS4), referred as “no further specification” Inhibitors,research,lifescience,medical (NFS) in this paper. There are differences in the volume of blood that attract “small/large (AIS4/5)” codes depending on the site of bleeding (Additional file 1). Subarachnoid haemorrhage Cytidine deaminase (SAH) was coded as present or absent. Data about the size of the haematoma refer to the “worst” CT scan information available. Potential confounders of the relationship between size of bleeding and patient outcome were selected for the multivariable analysis. These variables were: age, GCS, SAH, brain contusions, brain swelling, petechial haemorrhages, presence of other brain injuries (skull fractures and any brain lesion no further specified), presence of extracranial injuries (AIS with severity score >2), and whether or not the TBI patient has been treated at a neurosurgical unit (NSU). These variables have previously been reported to be associated with poor outcome.

from RNase in fecal samples precisely and could show that exosomal miRNA is more stable than free miRNA in a deadful condition like in feces. Acknowledgments We thank Professor Shigeru Kanaoka (Hamamatsu University School of Medicine) for his advice on fecal RNA extraction and Dr. Satoshi Katayose (JSR Corp.) for his technical support concerning immunomagnetic beads. We are also grateful to Mr. Suguru Fujisawa, Mr. Yohei Hisada, Ms. Satoe Miyaki, and Ms. Noriko F. Abe for their technical assistance, and to Ms. Kaoru Shiina for her secretarial assistance. Footnotes No potential conflict of interest. This work was supported by a Grant-in-Aid Inhibitors,research,lifescience,medical for the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan (to Y. Koga); Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to Y. Koga); the Innovation Promotion Program from the New Energy and Industrial Technology Development Organization Inhibitors,research,lifescience,medical (NEDO) of Japan (to Inhibitors,research,lifescience,medical Y. Matsumura);

and the Regional Innovation Cluster Program (City Area Type) (to Y. Matsumura).Colorectal cancer is diagnosed in approximately one million people worldwide each year, making it the third most common malignancy (1). Not unexpectedly, early diagnosis is associated with a better prognosis. Five-year survival rates of stage I and II colorectal cancer are in excess of 70%. However, in spite of advances in treatment, metastatic colorectal cancer has a five-year survival rate of less than 10% and is not considered a curative disease (2). Among the “holy grails” of cancer diagnostics is the discovery of novel, cost-effective Inhibitors,research,lifescience,medical biomarkers of sufficient sensitivity and specificity to permit detection in a more timely fashion. Additionally, biomarkers that provide prognostic information and

help clinicians to tailor cancer treatment and monitor response to treatment would be of considerable value. For example, mutations of the K-Ras gene, which Inhibitors,research,lifescience,medical are present in 40% of patients with metastatic colorectal cancer, have been found to be predictive of a poor response to these EGFR-targeted drugs (3). Cellular vesicles are among the newer biomarkers that have been described in the literature, not only for cancer, but for a variety of human AZD8055 research buy diseases. Cellular vesicles are shed from a variety of cell types and since they contain cell membrane and cytoplasm, their contents are reflections of their cell of origin. Vesicles arising from platelets and red blood cells were among the first to be described several decades ago, but their biological significance was not known initially. Chargaff and West were among the first to report the procoagulant properties of these entities as they observed that the high speed centrifugate of human cell and platelet-free plasma normalized clotting of blood from a patient with hemophilia (4).